The concept of targeting cancer therapeutics towards specific mutations or abnormalities in tumor cells which are not found in normal tissues has the potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. At least 30% of all human malignancies display activating mutations in the p21Ras genes, and perhaps another 60% display other activating mutations or over- activity of p21Ras-signaling pathways. We previously discovered that over-activity of p21Ras signaling sensitizes tumor cells to apoptosis induced by suppression of PKC? activity, which is not toxic to cells with normal levels of p21Ras activity. This property, designated "Ras-mediated apoptosis", can be exploited as a targeted cancer therapeutic. We have characterized Ras-mediated apoptosis molecularly, demonstrated its selectivity in vitro and in vivo, identified the specific target PKC isozyme (PKC?), identified two lead compounds for inducing cell death in tumors containing activated Ras or Ras pathways, and gained intellectual property protection on Ras-mediate apoptosis as a therapeutic. In this Phase I STTR application, we will refine and explore Lead Compound I by generating specific analogs, and use in vitro and in vivo studies to select the optimal inducer of Ras-mediated apoptosis. Assays will include assessment of PKC? specificity, targeting of cytotoxicity for cells expressing an activated Ras protein, and xenograft tumor models. We will then move this compound forward into formal preclinical studies. PUBLIC HEALTH RELEVANCE: Mutation or activation of Ras or Ras-directed signaling pathways occur in up to 70% of human malignancies, and the applicant organization has developed a therapeutic strategy by which programmed cell death can be induced in tumors with activation of Ras or Ras pathways. This Phase I STTR proposal is to carry out further preclinical testing of the current lead drug candidate, and analogs of this compound, to select the optimal compound to move into clinical trials. Successful development of this therapeutic could allow normal survival of many patients who would otherwise die of their disease, and could reduce annual medical care costs by billions of dollars.